Is NOTCH2 p.Pro2013Ser (c.6037C>T) pathogenic?

NOTCH2 p.Pro2013Ser (c.6037C>T) is classified Uncertain significance in NOTCH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-14). AlphaMissense: likely pathogenic (0.9598); Very rare (popmax 0.00153%, nfe); Associated with acroosteolysis dominant type.

What condition is associated with NOTCH2 p.Pro2013Ser (c.6037C>T)?

NOTCH2 p.Pro2013Ser (c.6037C>T) is associated with acroosteolysis dominant type (ClinVar).

How common is NOTCH2 p.Pro2013Ser (c.6037C>T) in the general population?

NOTCH2 p.Pro2013Ser (c.6037C>T) is very rare (popmax 0.00153%, nfe) (gnomAD).

What do computational predictors say about NOTCH2 p.Pro2013Ser (c.6037C>T)?

AlphaMissense predicts likely pathogenic (score 0.9598) — an in-silico prediction, not a clinical call.

NOTCH2 p.Pro2013Ser

c.6037C>T · VCV4739543

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9598 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00153%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

acroosteolysis dominant type

Computational evidence

Protein change
AlphaMissense	0.9598	likely pathogenic
REVEL	0.743	pathogenic-leaning
SaProt	LLR -12.16	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	phastCons 1
Regional constraint	o/e 0.50	unconstrained · MANE · 2,948 bp · p 1.3e-15 · regional, not allelic
Overall
CADD	25.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00153% European (non-Finnish) · 18/1,180,028 alleles

Filtering AF 0.000953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00123% 18/1,461,858 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: NOTCH2
Protein: p.Pro2013Ser
Coding: c.6037C>T
MANE Select: NM_024408
Type: single nucleotide variant
Location: chr1:119916685 (GRCh38)
Gene constraint: LOEUF 0.151 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.51 · 2 PDB

Full NOTCH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

acroosteolysis dominant type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NOTCH2 p.Arg2003Ter Pathogenic/Likely pathogenic ★★ same condition
NOTCH2 p.Arg2400Ter Pathogenic ★★ same condition
NOTCH2 p.Gln2223Ter Pathogenic ★★ same condition
NOTCH2 p.Gln2263Ter Pathogenic ★★ same condition
NOTCH2 p.Gln2285Ter Pathogenic/Likely pathogenic ★★ same condition
NOTCH2 c.2753-8T>A Uncertain significance ★★ same condition
NOTCH2 c.5214-10A>G Uncertain significance ★★ same condition
NOTCH2 c.874+4T>C Uncertain significance ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/notch2-p-pro2013ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown